Nothing Special   »   [go: up one dir, main page]

EP2819659B1 - Procédé de fabrication de nanoparticules chargées d'une substance active - Google Patents

Procédé de fabrication de nanoparticules chargées d'une substance active Download PDF

Info

Publication number
EP2819659B1
EP2819659B1 EP13703735.4A EP13703735A EP2819659B1 EP 2819659 B1 EP2819659 B1 EP 2819659B1 EP 13703735 A EP13703735 A EP 13703735A EP 2819659 B1 EP2819659 B1 EP 2819659B1
Authority
EP
European Patent Office
Prior art keywords
acid
polyethylene glycol
active compound
process according
organic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP13703735.4A
Other languages
German (de)
English (en)
Other versions
EP2819659A1 (fr
Inventor
Markus Weigandt
Senta VOSS
Tobias Miller
Achim Goepferich
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP2819659A1 publication Critical patent/EP2819659A1/fr
Application granted granted Critical
Publication of EP2819659B1 publication Critical patent/EP2819659B1/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the present invention relates to a novel process for the preparation of drug-loaded nanoparticles and their use as medicaments.
  • Nanoparticles are an innovative approach to the controlled release of pharmaceutical agents.
  • Polymer-based nanoparticles in particular, have found great interest in recent decades.
  • the drug (s) are embedded in a polymer matrix and are / are released in a controlled manner depending on the nature of the matrix.
  • the main advantages of such systems are: 1) increase in the solubility of hydrophobic drugs, 2) reduction of undesired side effects through target-specific release, 3) control of drug pharmacokinetics by the drug carrier, and 4) prevention of premature drug degradation after injection.
  • the amount of polymer in the nanoparticles increases the total amount required for its therapeutic administration compared to the sole administration of the active substance. It is therefore desirable to use nanoparticles with the highest possible drug loading, ie. the highest possible ratio of active ingredient to the excipient.
  • nanoparticle candidate excipients are polylactic acid, polylactic acid-co-glycolic acid or polycaprolactone.
  • Nanoparticles based on polymers can be prepared by various methods.
  • the manufacturing methods are:
  • Polymer and active ingredient are dissolved in a water-immiscible organic solvent, in particular dichloromethane, and introduced under constant agitation / stirring in an aqueous phase. From the resulting emulsion, the organic solvent is then removed either under vacuum or at normal pressure (see Example VPSant, D. Smith, and JCLeroux. Enhancement of oral bioavailability of poorly water-soluble drugs by poly (ethylene glycol) -block-poly (alkyl acrylate-co-methacrylic acid) self-assemblies. J Control Release. 104: 289-300 (2005 )). During this process, the loaded nanoparticles are formed.
  • a water-immiscible organic solvent in particular dichloromethane
  • W / O / W emulsion techniques are particularly suitable for the production of nanoparticles with rather hydrophilic and thus water-soluble active ingredients.
  • the polymer is dissolved in a non-water-miscible solvent (eg dichloromethane) and combined with an aqueous phase containing the dissolved active ingredient.
  • the combined phases are homogenized (eg by stirring or sonication) to give a W / O emulsion.
  • the W / O emulsion is then poured into an aqueous Phase injected, which contains an additional emulsifier as a stabilizer.
  • the solvent is again removed under vacuum or normal pressure ( K. Avgoustakis, A. Beletsi, Z. Panagi, P.
  • drug and polymer are mixed in an organic solvent and injected into the aqueous phase.
  • the organic solvent is removed in vacuo or at normal pressure.
  • the solvent used here is completely miscible with water, so that no emulsions are formed.
  • active ingredient and polymer are dissolved in a water-miscible organic solvent and introduced into a dialysis machine.
  • Dialysis can be done against water or buffer.
  • the preparation of the nanoparticles is carried out by slow, steady exchange of the solvent following the concentration gradient of the inner and outer phase.
  • the dialysis membranes used are permeable to small molecules (active ingredient), but the polymer remains in the inner phase due to the exclusionary factors ( HJJeon, JIJeong, MKJang, YHPark, and JWNah. Effect of solvent on the preparation of surfactant-free poly (DL-lactide-co-glycolide) nanoparticles and norfloxacin release characteristics. International Journal of Pharmaceutics. 207: 99-108 (2000 )).
  • This method is a standard for the preparation of liposomal formulations.
  • the lipid or polymer is dissolved in an organic solvent and evaporated under vacuum.
  • the film forming in the glassware is then reconstituted with buffer, drug solution or water.
  • a disadvantage is that the resulting polymer active substance film can not or only partially be redispersible ( A. Richter, C. Olbrich, M. Krause, J. Hoffmann, and T. Kissel. Polymeric micelles for parenteral delivery of sagopilone: physicochemical characterization, novel formulation approaches and their toxicity in vitro as well as in vivo. Eur J Pharm Biopharm. 75: 80-89 (2010 )).
  • the process usually follows a step of size classification (membrane extrusion, ultrasound treatment) after production of the raw particles ( E. Blanco, EABey, Y.Dong, BDWeinberg, DMSutton, DABoothman, and J.Gao. Beta-lapachone-containing PEG-PLA polymer micelles as novel nanotherapeutics against NQO1 overexpressing tumor cells. J Control Release. 122: 365-374 (2007 ); Richter et al. as cited above).
  • Lamprecht A. et al. describes dialysis of nanoparticles against pure water to remove excipients and unencapsulated drug ( Alf Lamprecht A. et al. Design of rolipram-loaded nanoparticles: comparison of two preparation methods. J Contr Release 71 (2001) 297-306 ) K. Elkharraz E. et al. Describes the preparation of drug-free and paclitaxel-loaded PLGA microparticles with an oil-in-water (O / W) solvent extraction / evaporation method ( Paclitaxel-Ioaded microparticles and implants for the treatment of brain cancer: Preparation and physicochemical characterization. Int J Pharm 314 (2006) 127-136 ).
  • nanoparticles Due to the embedding of the active ingredient in the polymer, the known processes also lead to nanoparticles, from which the active substance is released only with a certain time delay (lag time). As a result, after the administration of the nanoparticles, therapeutic drug levels are only reached with a time delay, so that in order to achieve a rapid onset of action the additional administration of the active ingredient in a readily available form is required. Therefore, nanoparticles which release an amount of active substance directly after administration would be desirable, so that the active substance is made available in a therapeutic amount from the polymers even before the delayed release of the active ingredient.
  • the method should enable the provision of nanoparticles which have higher drug loadings than nanoparticles prepared by conventional methods and conventional polymers. Furthermore, the produced Nanoparticles release immediately after their administration an initial dose of the drug and thus lead to a timely onset of action.
  • a method for producing nanoparticles comprising the following steps: (a) dissolving at least one active substance and at least one polymer in an organic solvent, (b) mixing the solution prepared in step (a) with a (c) evaporating the organic solvent, (d) purifying the drug-loaded nanoparticles obtained in step (c) by dialysis against the same active ingredient-containing aqueous dialysis solution.
  • the invention therefore provides a process for the preparation of nanoparticles comprising the steps of (a) dissolving at least one active ingredient and at least one polymer in an organic solvent, (b) mixing the solution prepared in step (a) with an aqueous phase, (c Evaporating the organic solvent, (d) purifying the drug-loaded nanoparticles obtained in step (c) by dialysis against the same active ingredient-containing aqueous dialysis solution.
  • the solution formed by dissolving the active substance and the polymer in an organic solvent according to step (a) is also referred to above and below as the organic phase.
  • aqueous phase water can be used in which water-soluble substances, in particular salts, such as buffer salts, acids or bases are dissolved.
  • the mixing of the solution prepared according to step (a) with the aqueous phase can be carried out by adding the solution prepared according to step (a) to the aqueous phase or adding the aqueous phase to the solution prepared according to step (a).
  • the addition of one solution to the other preferably takes place with constant stirring or shaking and optionally with the use of ultrasound. Conveniently, during mixing, the smaller volume phase of the larger volume phase is added, but the reverse procedure is also possible.
  • the aqueous phase consists of an aqueous solvent.
  • An "aqueous solvent” within the meaning of the invention is water, which may contain dissolved substances herein, in particular, electrolytes, such as, for example, salts, acids or bases.
  • the removal of the organic solvent can be carried out by evaporation under normal conditions, ie at room temperature and normal pressure, and can be accelerated by increasing the temperature and / or reducing the pressure, ie by lowering the pressure below the air pressure.
  • the evaporation is carried out at elevated temperature, more preferably at 30 to 60 ° C and / or at reduced pressure, preferably at 10 -4 to 80 mbar.
  • the evaporation can be done for example with a rotary evaporator.
  • Dialysis can be carried out with the usual dialyzer devices known to the person skilled in the art, for example with a dialysis tube customary in the laboratory.
  • the pore size of the dialysis membrane is selected so that the organic solvent and the active ingredient can pass freely through the dialysis membrane, but not the polymer.
  • the upper molecular weight cutoff (MWCO) of a suitable dialysis membrane is therefore preferably above the molecular weight of the active ingredient and the solvent but below the molecular weight of the smallest polymer molecules contained in the polymer.
  • a dialysis membrane having an MWCO below 5 kDa and above 1.5 kDa can be used.
  • a dialysis membrane having a MWCO of 3.5 kDa or 5 kDa can be used.
  • the dialysis solution contains no active ingredient, dialysis results in a concentration due to the concentration differences between the side containing the nanoparticles and the side containing the dialysis solution Reduction of active substance from the side containing the nanoparticles. Due to the loss of active ingredient in the solvent surrounding the nanoparticles, there is a strong difference in the concentration of active ingredient of the nanoparticles with respect to this solvent, with the result that drug can escape from the nanoparticles and then passes to the dialysis solution due to the concentration gradient and is transported away. By the use according to the invention of dialysis solution in which the active substance is dissolved, this concentration gradient is at least reduced and thus the loss of active ingredient from the nanoparticles is counteracted.
  • the active ingredient may be present in the dialysis solution in all concentrations up to its maximum solubility (saturation solubility) in the dialysis solution, preferably the dialysis solution is saturated with active ingredient.
  • the dialysis membrane is therefore brought into contact with active substance-containing dialysis solution, preferably with a dialysis solution saturated with active substance, before the dialysis is carried out, so that the membrane accumulates in accordance with the active substance concentration contained in the dialysis solution with active ingredient.
  • dialysis is carried out against dialysis solution saturated with active substance and with a dialysis membrane saturated with active substance.
  • the nanoparticles prepared according to the present method further have an amount of active substance adsorbed on the nanoparticles.
  • This proportion of active ingredient is advantageously available directly as an initial dose when administered to the patient.
  • the dialysis solution contains not only the active substance but also dissolved substances, in particular electrolytes, particularly preferably buffers and / or salts, which are also used in the the administration of the nanoparticles provided formulation should be included. Due to the fluid exchange due to dialysis, nanoparticles which are already contained in a suitable solvent for administration to the patient can be obtained in this way advantageously and in a simple manner. Before administration to the patient, therefore, only the sterility must be ensured, which can be done, for example, and in a simple manner by means of sterile filtration. Alternatively, the entire production process can be carried out under aseptic conditions, so that subsequent sterilization is not required.
  • the nanoparticles are present in the aqueous solvent. If, as described above, the nanoparticles are obtained in a suitable for administration to the patient solvent, when administered to the patient in addition to adsorbed to the nanoparticles drug also in the solvent dissolved drug is available as an initial dose.
  • the aqueous solvent removed which can be done for example preferably by freeze-drying or by spray drying, precipitated in the solvent dissolved active ingredient during dehydration at least partially on the nanoparticles, so this also when administered to the patient is available as an initial dose.
  • Active substances with a low saturation solubility in water preferably with a saturation solubility ⁇ 200 ⁇ g / ml, particularly preferably with a saturation solubility ⁇ 100 ⁇ g / ml, are preferably used in the process according to the invention (measured in each case at 25 ° C.).
  • the invention therefore also provides a process which is characterized in that the active substance in water has a saturation solubility ⁇ 200 ⁇ g / ml, preferably a saturation solubility ⁇ 100 ⁇ g / ml, in each case measured at 25 ° C.
  • active ingredients are active substances selected from the group consisting of chemotherapeutic agents, in particular taxol, camptothecin, platinum complexes or N-lost compounds, antirheumatics, such as, for example, glucocorticoids, in particular dexamethasone, mometasone, beclomethasone or prednisolone, anti-infective agents, such as, for example, HIV.
  • chemotherapeutic agents in particular taxol, camptothecin, platinum complexes or N-lost compounds
  • antirheumatics such as, for example, glucocorticoids, in particular dexamethasone, mometasone, beclomethasone or prednisolone
  • anti-infective agents such as, for example, HIV.
  • Therapeutics in particular ritonavir, as well as antimycotics, in particular ketoconazole, itraconazole, griseofulvin, lipid-lowering agents, such as fenofibrate, antioxidants and vitamins, such as tocopherol, retinoic acid, cholecalciferol, antibiotics, such as vancomycin or teicomycin, in addition cholesterol and fatty acids.
  • the invention therefore furthermore relates to a process which is characterized in that the active substance used is an active substance which is selected from the group consisting of chemotherapeutic agents, in particular taxol, camptothecin, platinum complexes or N-lost compounds, antirheumatics, such as, for example Glucocorticoids, in particular dexamethasone, mometasone, beclomethasone or prednisolone, anti-infective agents, such as HIV therapeutics, in particular ritonavir, as well as antimycotics, in particular ketoconazole, itraconazole, griseofulvin, lipid-lowering agents, such as fenofibrate, antioxidants and vitamins, such as tocopherol, retinoic acid -, cholecalciferol, antibiotics, such as vancomycin or teicomycin, in addition to cholesterol and fatty acids.
  • chemotherapeutic agents in particular taxol, camptothecin, platinum complexes or
  • an amphiphilic polymer is used as the polymer in the process.
  • the invention therefore also relates to the process according to the invention, which is characterized in that an amphiphilic polymer is used as the polymer.
  • Amphiphilic polymers are composed of a hydrophilic ("water-loving") and a hydrophobic ("water-harboring") parts. Due to this structure, amphiphilic polymers are deposited in heterogeneous mixtures of water and water-immiscible solvents, especially organic solvents, such as Dichloromethane, preferably at the interfaces between the aqueous and the organic phase to.
  • block copolymers are used as amphiphilic polymers.
  • the invention therefore also provides a process which is characterized in that a block copolymer is used as the polymer.
  • Block copolymers consist of one or more, also different blocks of a hydrophilic component a) and a hydrophobic component b), wherein the individual blocks may contain the same monomers with the same or different chain length or different monomers.
  • the components a) and b) can be linear or branched, comb-shaped or star-shaped simultaneously or independently of one another.
  • Component b) can also be a crosslinked polymer.
  • Particularly suitable hydrophobic component b) are biodegradable polymers such as, for example, polyesters, poly- ⁇ -caprolactone, poly- ⁇ -hydroxyesters, poly- ⁇ -hydroxyesters, polyanhydride, polyamide, polyphosphazene, polydioxanone, polyamic acid, polyuric acid, polyorthoesters, polycarbonate, polysaccharide , Peptide and protein.
  • biodegradable polymers such as, for example, polyesters, poly- ⁇ -caprolactone, poly- ⁇ -hydroxyesters, poly- ⁇ -hydroxyesters, polyanhydride, polyamide, polyphosphazene, polydioxanone, polyamic acid, polyuric acid, polyorthoesters, polycarbonate, polysaccharide , Peptide and protein.
  • hydrophilic component a) is composed of at least bifunctional and preferably water-soluble building blocks
  • suitable polymers are polyethylene glycols, polyacrylamides, polyvinyl alcohol, polysaccharides (for example, modified celluloses and starches), alginates, peptides and proteins.
  • Block copolymers which can be used according to the invention can be used as the hydrophilic component, for example polyethylene glycol, polypropylene glycol, polybutylene glycol, polyacrylamide, polyvinyl alcohol, polysaccharide or a copolymer thereof, preferably polyethylene glycol / polypropylene glycol copolymer, polyethylene glycol / polypropylene glycol / polyethylene glycol copolymer, and as hydrophilic component polylactic acid, polyglycolic acid, polyhydroxybutyric acid, Polyhydroxyvaleric acid, or a copolymer thereof, preferably polylactic-co-glycolic acid, furthermore polyacrylic acid, in particular hydroxypropylethylacrylic acid or hydroxypropylmethylacrylic acid, polysiloxane, in particular copolymers with acrylic acid, polystyrene or a copolymer thereof, in particular with polylactic acid and polyglycolic acid.
  • hydrophilic component for example polyethylene glycol, poly
  • the invention therefore also provides a process which is characterized in that the block copolymer as the hydrophilic component is polyethylene glycol, polypropylene glycol, polybutylene glycol, polyacrylamide, polyvinyl alcohol, polysaccharide or a copolymer thereof, preferably polyethylene glycol / polypropylene glycol copolymer, polyethylene glycol / polypropylene glycol / polyethylene glycol Copolymer, and as the hydrophobic component polylactic acid, polyglycolic acid, polyhydroxybutyric acid, polyhydroxyvaleric acid, or a copolymer thereof, preferably polylactone-co-glycolic acid, furthermore polyacrylic acid, in particular hydroxypropylethylacrylic acid or hydroxypropylmethylacrylic acid, polysiloxane, in particular copolymers with acrylic acid, polystyrene or a copolymer thereof, in particular with polylactic acid and polyglycolic acid.
  • polyethylene glycol-polylactic acid, polyethylene glycol-polyglycolic acid, polyethylene glycol-polylactic acid-co-glycolic acid, polyethylene glycol-polyhydroxyvaleric acid, polyethylene glycol-polysiloxane, polyethylene glycol-polysiloxane-co-acrylic acid, polyethylene glycol-polymethyl methacrylic acid, polyethylene glycol-polymethyl acid are used as block copolymers.
  • the invention therefore also provides a process which is characterized in that the block copolymers used are polyethylene glycol polylactic acid, polyethylene glycol-polyglycolic acid, polyethylene glycol-polylactic acid-co-glycolic acid, polyethylene glycol-polyhydroxyvaleric acid, polyethylene glycol-polysiloxane, polyethylene glycol-polysiloxane-co-acrylic acid, polyethylene glycol -Polymethylmethacrylklare, Polyethylene glycol-polymethyl-ethacrylic acid, polyethylene glycol-polyisoprylacrylic acid, polyethylene glycol polystyrene is used.
  • the block copolymers used are polyethylene glycol polylactic acid, polyethylene glycol-polyglycolic acid, polyethylene glycol-polylactic acid-co-glycolic acid, polyethylene glycol-polyhydroxyvaleric acid, polyethylene glycol-polysiloxane, polyethylene glycol-polysiloxane-co-
  • a solvent which is at least partially miscible with water, preferably completely miscible is used as the organic solvent in the process according to the invention.
  • the invention therefore also provides a process which is characterized in that a solvent which is at least partially miscible with water, preferably completely miscible, is used as the organic solvent.
  • a solvent which is at least partially miscible with water is a solvent which can be mixed at room temperature (25 ° C.) to obtain a uniform, homogeneous phase of water in a volume ratio of at least 40/60 v / v (organic solvent / water) , If the maximum water content that can be mixed while maintaining a homogeneous phase is exceeded, a phase separation occurs between the homogeneous organic phase containing water and water and a second phase consisting of water.
  • a fully water-miscible organic solvent is an organic solvent which is water-miscible at room temperature (25 ° C) to obtain a uniform, homogeneous phase.
  • Organic solvents which can be used in the process according to the invention are linear or branched-chain alcohols, preferably methanol, ethanol, isopropanol, n-butanol or tert-butanol, acetone, dimethylformamide, tetrahydrofuran or dimethyl sulfoxide.
  • the invention therefore also provides a process which is characterized in that the organic solvent used is linear or branched-chain alcohols, preferably methanol, ethanol, isopropanol, n-butanol or tert-butanol, acetone, dimethylformamide, tetrahydrofuran or dimethyl sulfoxide.
  • Active substances which are acids or bases can preferably be added according to the invention to increase their solubility in each case in a complementary manner with a base or an acid. If the active substance is an acid, then a base is added to it, if it is a base, the addition of an acid takes place.
  • the acid or base can be added in the process according to claim 1 in step (a) or in step (b).
  • the invention therefore also an embodiment of the method according to the invention, which is characterized in that in step (a) according to claim 1 in the organic solvent in addition to polymer and active ingredient an acid or a base is dissolved and / or that in the aqueous solvent according to Step (b) of claim 1, an acid or a base is dissolved.
  • Suitable acids are organic acids, preferably formic acid, acetic acid or trifluoroacetic acid, or inorganic acids, preferably hydrochloric acid, nitric acid or sulfuric acid
  • suitable bases are organic bases, preferably dimethylamine or trimethylamine or inorganic bases, preferably sodium hydroxide, potassium hydroxide or ammonia.
  • the invention therefore also relates to a process which is characterized in that the acid is an organic acid, preferably formic acid, acetic acid or trifluoroacetic acid, or an inorganic acid, preferably hydrochloric acid, nitric acid or sulfuric acid, and the base is an organic base, preferably dimethylamine or Trimethylamine or an inorganic base, preferably sodium hydroxide, potassium hydroxide or ammonia.
  • the acid is an organic acid, preferably formic acid, acetic acid or trifluoroacetic acid, or an inorganic acid, preferably hydrochloric acid, nitric acid or sulfuric acid
  • the base is an organic base, preferably dimethylamine or Trimethylamine or an inorganic base, preferably sodium hydroxide, potassium hydroxide or ammonia.
  • the organic solvent used for dissolving active ingredient and polymer is selected as described below.
  • solvents which are at least partially miscible with water
  • the choice of solvents contains, for example, alcohols (methanol, ethanol, isopropanol, 1-propanol, tert-butanol), dimethylsulfoxide (DMSO), dimethylformamide (DMF), dioxane, tetrahydrofuran (THF), acetonitrile (ACN) and acetone.
  • the active substance is an acid or base, these are preferably mixed in each case with an acid or a base according to the procedure described above.
  • the active ingredient is insoluble in an organic solvent, this solvent is less suitable for the production of nanoparticles. If a clear solution is obtained, the same defined amounts of aqueous solvent are added step by step for as long as possible, and in each case mixed until after addition and mixing a precipitation of the active substance is optically recognizable (optical solubility).
  • the assessment of the optical solubility is carried out visually in a suitable container, preferably in a glass tube with a small diameter, for example as used in gas chromatography (diameter of 0.5 cm, 3 cm height) in cold light, which preferably radiates above, against a dark surface, preferably against a black surface, as a background.
  • a schematic representation of the procedure is in illustration 1 shown.
  • the aqueous solvent used is an aqueous solvent which has the same composition as the aqueous solvent used in the process according to step (b) according to claim 1.
  • the organic solvent to which the highest proportion of aqueous solvent is miscible without the active substance precipitating out of the solution is particularly suitable for use in the process according to the invention.
  • the present invention is therefore also an embodiment of the method, which is characterized in that in the preparation of the nanoparticles according to step (a) of claim 1 as an organic solvent, that organic solvent is used, in the preparation of a drug in a defined amount containing Solution in comparison to this active ingredient in each case the same amount containing solutions in other organic solvents with successive admixture of aqueous solvent, the highest proportion of aqueous solvent is immiscible without the active ingredient precipitates out of the solution.
  • Evaporation of the organic solvent according to step (c) of claim 1 from the solvent mixture prepared according to step (b) results in a continuous reduction in the solubility of the active ingredient and polymer in the solvent mixture due to the reduction of the organic solvent content in the solvent mixture. If, for an organic solvent in mixture with the aqueous solvent in evaporation already at low decrease of its content in the solvent mixture too low a solubility for the active ingredient, the active ingredient precipitates already at a time when the polymer is still completely or substantially dissolved and no nanoparticles are formed yet. If the active substance precipitates before the nanoparticles are formed, it can no longer be trapped in the polymer. so that in the course of further evaporation nanoparticles are obtained in which little or no active ingredient is embedded.
  • the highest proportion of aqueous solvent, the period in which the active ingredient is present during the evaporation in solution, prolonged and early unwanted drug precipitation can be avoided. Due to the prolonged period in which the active ingredient is in solution during the evaporation, it is preferable to first form the nanoparticles, which at the same time include part of the active ingredient. As evaporation progresses, the decreasing level of organic solvent in the mixture is no longer sufficient to keep the active ingredient in solution by the co-solvent effect. Finally, the unencapsulated drug is distributed in this process into the hydrophobic core of the nanoparticles.
  • the method for determining the organic solvent with the organic solvents methanol, ethanol, isopropanol, n-butanol, tert-butanol, acetone, dimethylformamide, tetrahydrofuran and dimethyl sulfoxide.
  • the invention therefore also an embodiment of the method according to the invention, which is characterized in that are used as organic solvents, methanol, ethanol, isopropanol, n-butanol, tert-butanol, acetone, dimethylformamide, tetrahydrofuran and dimethyl sulfoxide.
  • the amount of aqueous phase is therefore chosen so that after mixing the organic and aqueous phase according to step (b) of claim 1, the aqueous phase is present in relation to the organic phase in an amount which is below the amount which is the maximum immiscible organic phase, without the drug is no longer completely dissolved.
  • the invention therefore also an embodiment of the method, which is characterized in that the amount of aqueous phase is selected so that after mixing the organic and aqueous phase according to step (b) of claim 1, the aqueous phase in relation to the organic Phase is present in an amount which is below the amount that is the maximum immiscible organic phase, without the drug is no longer completely dissolved.
  • aqueous phase in relation to the organic phase it is useful in the process to choose the amount of aqueous phase in relation to the organic phase so that it is well below the amount that is the maximum immiscible organic phase , without the active ingredient is no longer completely dissolved.
  • organic and aqueous phase in the cosolvent evaporation for example, in a volume ratio of 4: 1 v / v can be used, so that ensures both Components are completely dissolved.
  • the determination of the maximum amount of aqueous phase which can be added to the organic phase is carried out according to steps (a) to (d) of the method for determining the organic solvent described on page 17.
  • the invention therefore also provides an embodiment which is characterized in that the determination of the maximum amount of aqueous phase which can be added to the organic phase in accordance with steps (a) to (d) of page 17 described method for the determination of the organic solvent.
  • the implementation of the method according to the invention leads advantageously to nanoparticles with increased drug loading and biphasic drug release, wherein after administration, first a rapid drug release (initial dose), which is followed by a sustained release over a longer period of time.
  • the invention therefore also nanoparticles, which are characterized in that they were prepared according to the inventive method.
  • the active ingredients dexamethasone and 5- [2- (2-fluoro-phenyl) - [1,8] naphthyridin-4-yl] - [2,6] naphthyridin-1-ylamine (hereinafter also called drug B) were used .
  • the active compounds were each dissolved at a concentration of 1 mg / 100 ⁇ L in the following solvents: tetrahydrofuran (THF), acetonitrile (ACN), acetone, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), methanol, ethanol.
  • 0.1% trifluoroacetic acid (v / v) was added to each organic solution of drug B to establish an apparent "pH".
  • the solutions were each successively with 10 ⁇ L of water and mixed until the drug began to precipitate (optical solubility).
  • Figure 2 shows the optical solubility of dexamethasone
  • Figure 3 the optical solubility of drug B.
  • this solvent was chosen as the organic solvent for the preparation of the nanoparticles.
  • the starting ratio was set at 4: 1 v / v (THF: water).
  • PEG-PDLLA [5-b-23]
  • PEG-PCL [5-b-32.5]
  • PEG-PVPy [5-b-20] from Polymersource Inc., Montreal, Canada.
  • PEG-PLGA [5-b-28] (Resomer RGP 50155 d) from Boehringer Ingelheim, Ingelheim, Germany. All polymers were of research grade.
  • nanoparticles prepared by the various methods were characterized in terms of their active ingredient loading and particle sizes and their size distributions.
  • micellar formulation 100 ⁇ L of the resulting micellar formulation was dissolved in 900 ⁇ L acetonitrile. This solution was detected on a HPLC system (Merck Hitachi La Chrom Elite) via a UV detector (detection wavelength: 282 nm). The separation was carried out on an Agilent Eclipse Plus C18 column (3.5 ⁇ m grain size, 5 cm length) at 30 ° C. A gradient method was used for the separation. The mobile phase A consisted of 90% acetonitrile and 10% ammonium acetate buffer pH 4.5 (v / v), the mobile phase B had the reverse composition. The dexamethasone sample concentration was determined via a calibration curve.
  • the DLS technique determines the hydrodynamic particle radius or diameter.
  • the samples are diluted 1: 100 (v / v) with water and measured in a Malvern Zetasizer Nano ZS (Malvern Instruments Ltd., Worcestershire, UK) in the backscatter mode. Particle sizes were calculated by cumulant analysis.
  • the polydispersity index (Pdl, polydispersity index) was calculated, which is used as a measure of the scattering of the particle size distribution.
  • the PdI can have values between 0 and 1, where 0 means monodisperse and 1 (completely) polydisperse.
  • the preparation and loading of the nanoparticles was carried out according to the method described in this invention as a combination of cosolvent evaporation and dialysis against drug-saturated solution.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Inorganic Chemistry (AREA)
  • Hematology (AREA)
  • Virology (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Biomedical Technology (AREA)
  • Nanotechnology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Nutrition Science (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Claims (16)

  1. Procédé de production de nanoparticules, comprenant les étapes
    (a) de dissolution d'au moins un ingrédient actif et d'au moins un polymère dans un solvant organique,
    (b) de mélange de la solution préparée dans l'étape (a) avec une phase aqueuse,
    (c) d'évaporation du solvant organique,
    (d) de purification des nanoparticules chargées avec l'ingrédient actif obtenues dans l'étape (c) au moyen d'une dialyse contre une solution de dialyse aqueuse comprenant le même ingrédient actif.
  2. Procédé selon la revendication 1 et/ou 2, caractérisé en ce que l'ingrédient actif possède une solubilité à saturation dans l'eau < 200 µg/ml, préférablement une solubilité à saturation < 100 µg/ml, dans chaque cas mesurée à 25°C.
  3. Procédé selon la revendication 2, caractérisé en ce que l'ingrédient actif utilisé est un ingrédient actif qui est choisi dans le groupe constitué par les agents chimiothérapeutiques, en particulier le taxol, la camptothécine, les complexes de platine ou les composés de N-moutarde, les agents anti-rhumatismaux, tels que par exemple les glucocorticoïdes, en particulier la dexaméthasone, la mométasone, la béclométhasone ou la prednisolone, les agents anti-infectieux, tels que par exemple les agents thérapeutiques anti-VIH, en particulier le ritonavir, et les agents antimycotiques, en particulier le kétoconazole, l'itraconazole, la griséofulvine, les agents hypolipidémiants, tels que par exemple le fénofibrate, les antioxydants et les vitamines, tels que par exemple le tocophérol, l'acide rétinoïque, le cholécalciférol, les antibiotiques, tels que par exemple la vancomycine ou la teïcomycine, en outre le cholestérol et les acides gras.
  4. Procédé selon l'une ou plusieurs parmi les revendications 1 à 3, caractérisé en ce que le polymère employé est un polymère amphiphile.
  5. Procédé selon la revendication 4, caractérisé en ce que le polymère employé est un polymère bloc.
  6. Procédé selon la revendication 4 et/ou 5, caractérisé en ce que le copolymère bloc contient, comme composant hydrophile, du polyéthylène glycol, du polypropylène glycol, du polybutylène glycol, du polyacrylamide, de l'alcool polyvinylique, un polysaccharide ou un copolymère de ceux-ci, préférablement un copolymère de polyéthylène glycol-polypropylène glycol, un copolymère de polyéthylène glycol-polypropylène glycol-polyéthylène glycol, et, comme composant hydrophobe, de l'acide polylactique, de l'acide polyglycolique, de l'acide polyhydroxybutyrique, de l'acide polyhydroxyvalérique, ou un copolymère de ceux-ci, préférablement l'acide polylactique-co-glycolique, en outre de l'acide polyacrylique, en particulier l'acide hydroxypropyléthylacrylique ou l'acide hydroxypropyléthylacrylique, un polysiloxane, en particulier des copolymères avec l'acide acrylique, du polystyrène ou un copolymère de celui-ci, en particulier avec l'acide polylactique et l'acide polyglycolique.
  7. Procédé selon la revendication 6, caractérisé en ce que les copolymères blocs employés sont le polyéthylène glycol-acide polylactique, le polyéthylène glycol-acide polyglycolique, le polyéthylène glycol-acide polylactique-co-acide glycolique, le polyéthylène glycol-acide polyhydroxyvalérique, le polyéthylène glycol-polysiloxane, le polyéthylène glycol-polysiloxane-co-acide acrylique, le polyéthylène glycol-acide polyméthylméthacrylique, le polyéthylène glycol-acide polyméthyléthacrylique, le polyéthylène glycol-acide polyisopropylacrylique, le polyéthylène glycol-polystyrène.
  8. Procédé selon l'une ou plusieurs parmi les revendications 1 à 7, caractérisé en ce que le solvant organique utilisé est un solvant qui est au moins partiellement miscible, préférablement totalement miscible, avec l'eau.
  9. Procédé selon la revendication 8, caractérisé en ce que le solvant organique employé est constitué d'alcools à chaîne linéaire ou ramifiée, préférablement le méthanol, l'éthanol, l'isopropanol, le n-butanol ou le tertio-butanol, l'acétone, le diméthylformamide, le tétrahydrofurane ou le diméthylsulfoxyde.
  10. Procédé selon l'une ou plusieurs parmi les revendications 1 à 9, caractérisé en ce que, dans l'étape (a) selon la revendication 1, un acide ou une base est solubilisé(e) dans le solvant organique outre le polymère et l'ingrédient actif, et/ou en ce qu'un acide ou une base est solubilisé(e) dans le solvant aqueux dans l'étape (b) selon la revendication 1.
  11. Procédé selon la revendication 10, caractérisé en ce que l'acide est un acide organique, préférablement l'acide formique, l'acide acétique ou l'acide trifluoroacétique, ou un acide inorganique, préférablement l'acide chlorhydrique, l'acide nitrique ou l'acide sulfurique, et la base est une base organique, préférablement la diméthylamine ou la triméthylamine, ou une base inorganique, préférablement l'hydroxyde de sodium, l'hydroxyde de potassium ou l'ammoniaque.
  12. Procédé selon l'une ou plusieurs parmi les revendications 1 à 11, caractérisé en ce que le solvant organique utilisé dans la production des nanoparticules dans l'étape (a) selon la revendication 1 est le solvant organique avec lequel la plus grande proportion de solvant aqueux peut être mélangée lors de la préparation d'une solution comprenant l'ingrédient actif en quantité définie sans que ce dernier ne précipite dans la solution par rapport à des solutions comprenant cet ingrédient actif selon la même quantité dans chaque cas dans d'autres solvants organiques lors d'un mélange successif de solvant aqueux.
  13. Procédé selon la revendication 12, caractérisé en ce que le solvant organique est déterminé par la méthode suivante :
    (a) la préparation de solutions de l'ingrédient actif ayant la même proportion d'ingrédient actif dans chaque cas dans divers solvants organiques,
    (b) l'addition d'une quantité dans chaque cas identique de solution aqueuse à chacune des solutions préparées dans l'étape (a),
    (c) la vérification du fait que l'ingrédient actif est, ou non, dans chaque cas totalement solubilisé dans les solutions de l'étape (b),
    (d) la mise en oeuvre répétée des étapes (b) et (c) avec les solutions dans lesquelles l'ingrédient actif est totalement solubilisé dans l'étape (c), jusqu'à ce que l'ingrédient actif ne soit plus totalement solubilisé dans l'étape (c),
    (e) l'identification du solvant organique avec lequel la plus grande quantité de solution aqueuse peut être mélangée de manière cumulée dans l'étape (d) avant que l'ingrédient actif ne soit plus totalement solubilisé.
  14. Procédé selon la revendication 12 et/ou 13, caractérisé en ce que les solvants organiques employées sont le méthanol, l'éthanol, l'isopropanol, le n-butanol, le tertio-butanol, l'acétone, le diméthylformamide, le tétrahydrofurane et le diméthylsulfoxyde.
  15. Procédé selon l'une ou plusieurs parmi les revendications 1 à 14, caractérisé en ce que la quantité de phase aqueuse est choisie de sorte que, après mélange de la phase organique et aqueuse dans l'étape (b), la phase aqueuse soit présente selon une quantité, par rapport à la phase organique, qui est inférieure à la quantité maximale pouvant être mélangée avec la phase organique sans que l'ingrédient actif ne soit plus totalement solubilisé.
  16. Procédé selon la revendication 15, caractérisé en ce que la détermination de la quantité maximale de phase aqueuse pouvant être mélangée avec la phase organique est effectuée conformément aux étapes (a) à (d) selon la revendication 13.
EP13703735.4A 2012-02-29 2013-02-11 Procédé de fabrication de nanoparticules chargées d'une substance active Active EP2819659B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102012004099 2012-02-29
PCT/EP2013/000396 WO2013127490A1 (fr) 2012-02-29 2013-02-11 Procédé de fabrication de nanoparticules chargées d'une substance active

Publications (2)

Publication Number Publication Date
EP2819659A1 EP2819659A1 (fr) 2015-01-07
EP2819659B1 true EP2819659B1 (fr) 2018-05-30

Family

ID=47710089

Family Applications (1)

Application Number Title Priority Date Filing Date
EP13703735.4A Active EP2819659B1 (fr) 2012-02-29 2013-02-11 Procédé de fabrication de nanoparticules chargées d'une substance active

Country Status (9)

Country Link
US (1) US10561733B2 (fr)
EP (1) EP2819659B1 (fr)
JP (1) JP6229666B2 (fr)
CN (1) CN104136012B (fr)
AU (1) AU2013225389B2 (fr)
CA (1) CA2865700C (fr)
ES (1) ES2685743T3 (fr)
IL (1) IL233985B (fr)
WO (1) WO2013127490A1 (fr)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2309989B1 (fr) 2008-06-16 2016-09-07 BIND Therapeutics, Inc. Nanoparticules polymères pharmacologiquement chargées et leurs méthodes de fabrication et d'utilisation
WO2010005726A2 (fr) 2008-06-16 2010-01-14 Bind Biosciences Inc. Nanoparticules polymères thérapeutiques avec inhibiteurs de mtor et procédés de fabrication et d’utilisation associés
US8318211B2 (en) 2008-06-16 2012-11-27 Bind Biosciences, Inc. Therapeutic polymeric nanoparticles comprising vinca alkaloids and methods of making and using same
US8563041B2 (en) 2008-12-12 2013-10-22 Bind Therapeutics, Inc. Therapeutic particles suitable for parenteral administration and methods of making and using same
EP2379064B1 (fr) 2008-12-15 2020-02-26 Pfizer Inc. Longues nanoparticules circulantes pour la libération prolongée d'agents thérapeutiques
JP5891175B2 (ja) 2009-12-11 2016-03-22 バインド セラピューティックス インコーポレイテッド 治療用粒子の凍結乾燥に対する安定製剤
EP2515942B1 (fr) 2009-12-15 2020-02-12 Pfizer Inc. Compositions de nanoparticules polymères à visée thérapeutique à base de copolymères à température de transition vitreuse élevée ou poids moléculaires élevés
ES2732377T3 (es) * 2012-09-17 2019-11-22 Pfizer Procedimiento de preparación de nanopartículas terapéuticas
SI3311845T1 (sl) 2013-09-16 2020-06-30 Astrazeneca Ab Terapevtski polimerni nanodelci in postopki njihove izdelave in uporabe
AR099756A1 (es) 2014-03-14 2016-08-17 Pfizer Nanopartículas terapéuticas que comprenden un agente terapéutico, y métodos para su elaboración y uso, composición farmacéutica
CN105288631B (zh) * 2015-11-17 2018-10-30 杭州普施康生物科技有限公司 一种新型抗癌药物纳米制剂及其制备方法
CN105331065A (zh) * 2015-11-30 2016-02-17 南京邮电大学 一种包覆聚集诱导发光铂配合物的聚乙二醇-聚乳酸纳米材料及其制备方法和应用
KR102126984B1 (ko) * 2016-07-25 2020-06-26 주식회사 삼양바이오팜 생분해성 고분자의 정제 방법
WO2018183631A1 (fr) * 2017-03-29 2018-10-04 Phosphorex, Inc. Nouvelles formulations pharmaceutiques contenant de l'indirubine et des dérivés de celui-ci et procédés de fabrication et d'utilisation de celles-ci
AU2020360526A1 (en) * 2019-10-01 2022-05-26 Evonik Corporation Process for preparing nanoparticles in the form of a powder comprising a bio-resorbable polyester
US20230201116A1 (en) * 2020-06-02 2023-06-29 Purdue Research Foundation Forumulation of monodisperse kinetically frozen polymer micelles via equilibration-nanoprecipitation

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10351004A1 (de) * 2003-10-30 2005-05-25 Basf Ag Nanopartikuläre Wirkstoffformulierungen
WO2008124632A1 (fr) * 2007-04-04 2008-10-16 Massachusetts Institute Of Technology Nanoparticules assistées par des composés amphiphiles pour délivrance ciblée
JP2012505957A (ja) * 2008-10-15 2012-03-08 メディバス エルエルシー プロリンベースの生分解性ポリマー

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Also Published As

Publication number Publication date
CA2865700C (fr) 2020-05-05
WO2013127490A1 (fr) 2013-09-06
JP2015508787A (ja) 2015-03-23
IL233985B (en) 2021-01-31
CN104136012A (zh) 2014-11-05
ES2685743T3 (es) 2018-10-11
IL233985A0 (en) 2014-09-30
AU2013225389A1 (en) 2014-10-09
US20150051181A1 (en) 2015-02-19
US10561733B2 (en) 2020-02-18
JP6229666B2 (ja) 2017-11-15
AU2013225389B2 (en) 2017-05-11
CA2865700A1 (fr) 2013-09-06
EP2819659A1 (fr) 2015-01-07
CN104136012B (zh) 2019-07-12

Similar Documents

Publication Publication Date Title
EP2819659B1 (fr) Procédé de fabrication de nanoparticules chargées d&#39;une substance active
DE60100542T2 (de) Herstellungsverfahren von kolloidale systeme enthaltenden mikrokugeln
DE69526787T2 (de) Biokompatibele und biodegradierbare Nanokapseln zur Absorption und Verabreichung von proteinischen Arzneimitteln
DE60122335T2 (de) Zusammensetzung auf der basis polymerer mizellen
DE69632408T2 (de) Stabilisierte und steril filtrierbare nanopartikel
G Nava-Arzaluz et al. Single emulsion-solvent evaporation technique and modifications for the preparation of pharmaceutical polymeric nanoparticles
DE69617245T2 (de) Produkte mit gesteuerter freisetzung
DE69534780T2 (de) Flüssige Zusammensetzungen zur Arzneistoffabgabe
RU2523714C2 (ru) Полимерные системы доставки действующих веществ
EP1771157B1 (fr) Forme galenique multiparticulaire pour principes actifs faiblement solubles, et procede de production de la forme galenique
WO2000033820A2 (fr) Systemes noyau-coque nanoparticulaires et leur utilisation dans des preparations pharmaceutiques et cosmetiques
EP1978936A1 (fr) Compositions pharmaceutiques contenant des mélanges de polymères et d&#39;agents actifs peu solubles dans l&#39;eau
EP2408438A2 (fr) Matériaux composites chargés en produits thérapeutiques et de diagnostics comprenant des nanoparticules polymères et des fibres polymères
EP0615442B1 (fr) Matrice thermocollo dale reglee par des sols a base de gelatine utile dans des formes d&#39;administration perorale a action prolongee
DE60121574T2 (de) Festes dispersionssystem von pranlukast mit verbesserter auflösung und methode zu dessen herstellung
WO2004030649A2 (fr) Procede pour preparer et stabiliser des microsuspensions et des nanosuspensions au moyen d&#39;amphiphiles et de polyelectrolytes
WO2012160088A1 (fr) Nanoparticules et microparticules biocompatibles enrobées de stabilisateurs pour une application pulmonaire
DE602004006000T2 (de) Verringerung der teilchengrösse von bioaktiven verbindungen
KR20170113568A (ko) 폴리머 안정화된 약학 제제용 수중 유 에멀전의 제조
EP1487422B1 (fr) Films de revetement a liberation tres controlee et a grande stabilite
WO1994026267A1 (fr) Compositions sous forme de solutions solides
Slavkova et al. Formulation of Budesonide-Loaded Polymeric Nanoparticles into Hydrogels for Local Therapy of Atopic Dermatitis
DE112006000921T5 (de) Nanopartikuläre Zusammensetzungen zur kontrollierten Freisetzung, die Prostaglandin-Derivate umfassen
US10172867B2 (en) Afobazole nanoparticles formulation for enhanced therapeutics
KR20220065475A (ko) 펜벤다졸 가용화 조성물 및 이의 용도

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20140707

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

RIN1 Information on inventor provided before grant (corrected)

Inventor name: VOSS, SENTA

Inventor name: WEIGANDT, MARKUS

Inventor name: GOEPFERICH, ACHIM

Inventor name: MILLER, TOBIAS

DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20161207

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 31/573 20060101ALI20171107BHEP

Ipc: A61K 31/4375 20060101ALI20171107BHEP

Ipc: A61K 9/51 20060101AFI20171107BHEP

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTG Intention to grant announced

Effective date: 20180103

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

Free format text: NOT ENGLISH

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 1002860

Country of ref document: AT

Kind code of ref document: T

Effective date: 20180615

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

Free format text: LANGUAGE OF EP DOCUMENT: GERMAN

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 502013010254

Country of ref document: DE

REG Reference to a national code

Ref country code: NL

Ref legal event code: MP

Effective date: 20180530

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2685743

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20181011

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180830

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180830

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180530

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180530

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180530

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180530

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180530

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180530

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180530

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180831

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180530

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180530

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180530

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180530

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180530

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180530

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180530

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180530

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 502013010254

Country of ref document: DE

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20190301

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180530

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190211

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180530

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20190228

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180530

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190211

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190228

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180530

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 1002860

Country of ref document: AT

Kind code of ref document: T

Effective date: 20190211

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190211

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181001

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180530

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180930

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20130211

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180530

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230518

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20231221

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20231212

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20240304

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20231220

Year of fee payment: 12

Ref country code: CH

Payment date: 20240301

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20240111

Year of fee payment: 12